Hormone Therapy (HT) is commonly used to relieve the symptoms associated with menopause. Recent studies show HT is associated with an increased risk of breast cancer and cardiovascular disease (CVD). However, some women may have differing degrees of susceptibility to these HT-related risks, based on genetic background. The overall hypothesis of this study is that common genetic variants can be used to classify women into low or neutral risk groups for developing breast cancer due to HT use (gene-hormone interaction). We specially hypothesize that 1) a subset of genetic variants account for individual differences in risk of developing breast cancer upon HT use (E+P or E only) on breast cancer risk, 2) those SNPs may or may not alter the risk of developing CVD upon HT use. We will identify the genetic variants using data and samples from the Hormone Therapy Trial (HT) of the Women's Health Initiative (WHI) study, a large randomized, double-blind, placebo-controlled clinical trial, and perform a replication study in the WHI Observational Study (OS). To test these hypotheses, we have four specific aims. Aim 1 is to identify SNPs that account for individual differences in risk of developing breast cancer upon HT use (SNP-HT interactions). Aim 2 is to confirm the top significant SNPs identified in Aim 1 among women in the OS arm. Aim 3 is to evaluate the SNP-HT interaction with other phenotypes (primarily CVD) among women in the OS arm. Aim 4 is to estimate the individual absolute risk of developing breast cancer upon HT use among women in the OS arm. We expect to identify a subset of SNPs that alter the risk of developing breast cancer upon HT use Results from this study could benefit millions of women who suffer from menopausal symptoms. The identified genetic variants will be used to create a risk-benefit profile for HT treatment and may potentially improve clinical decision making for HT use. Individual HT-breast cancer risk assessment is important for identifying women for whom the benefits may outweigh the risks versus those women in whom the risks outweigh the benefits. PUBLIC HEALTH RELEVANCE: Hormone therapy (HT), the most commonly used approach to treat the symptoms associated with menopause, has been dropped because of the concerns of increased breast cancer and other health risk. Genetic variants which interact with hormone therapy can be used as markers to classify women into low or neutral risk groups for developing breast cancer with HT use. The identified genetic variants will be used to create a risk-benefit profile for HT treatment and improve clinical decision making for HT use.